Abstract
BACKGROUND: Adoptive cell transfer (ACT) is a promising cancer immunotherapeutic strategy that remains ineffective for a large subset of patients. ACT with memory CD8+ T cells (T(mem)) has been shown to have superior efficacy compared to traditional ACT with effector CD8+ T cells (T(eff)). T(eff) and T(mem) have complementary physiological advantages for immunotherapy, but previous publications have not examined ACT using a combination of T(eff) and T(mem). METHODS: Splenocytes harvested from Ly5.1+/C57BL/6 mice during and after infection with lymphocytic choriomeningitis virus (LCMV) were used to generate bona fide effector and memory CD8+ T cells specific for the LCMV epitope peptide GP33. Congenic Ly5.2+/C57BL/6 mice were inoculated with B16F10 melanoma cells transfected to express very low levels of GP33, then treated with ACT 7 days later with GP33-specific T(eff), T(mem), or a combination of T(eff) + T(mem). RESULTS: Inhibition of melanoma growth was strongest in mice receiving combinatorial ACT. Although combinatorial ACT and memory ACT resulted in maximal intratumoral infiltration of CD8+ T cells, combinatorial ACT induced stronger infiltration of endogenous CD8+ T cells than T(mem) ACT and a stronger systemic T cell responsiveness to tumor antigen. In vitro assays revealed rapid but transient melanoma inhibition with T(eff) and gradual but prolonged melanoma inhibition with T(mem); the addition of T(mem) enhanced the ability of T(eff) to inhibit melanoma in a manner that could be reproduced using conditioned media from activated T(mem) and blocked by the addition of anti-IL-2 blocking antibody. CONCLUSIONS: These findings suggest that a novel combinatorial approach that takes advantage of the unique and complementary strengths of tumor-specific T(eff) and T(mem) may be a way to optimize the efficacy of adoptive immunotherapy.